Regulation of blood flow is a central topic in cardiovascular biology. Many disorders involve dysfunctional flow regulation, and vasoactive drugs are frequently used in treating these disorders. Delivery of an adequate oxygen supply is the most critical function of the circulatory system. The overall objective of this project is to develop quantitative theoretical models for blood flow regulation and oxygen transport in microvascular networks. In prior studies supported by this grant, we developed a model for steady-state flow regulation in a network with a homogeneous structure. That model, which will form the basis for the proposed studies, has provided insights into the roles of myogenic, metabolic, shear-dependent and conducted responses and oxygen-dependent release of ATP by red blood cells in the regulation of flow. In the proposed work, we will examine the effects of heterogeneity, time-dependent behavior and capillary recruitment on flow regulation. Specific Aim 1 is to develop theoretical models for flow regulation in microvascular networks with inhomogeneous structures and spatially varying metabolic demand. The models will be used to investigate the mechanisms by which perfusion is locally matched to metabolic demand in normal tissue and how this fails in abnormal states. Specific Aim 2 is to develop theoretical models for time- dependent flow regulation in response to changes in metabolic demand and arterial pressure, and to apply this model to analyze spontaneous oscillations in arteriolar diameter and blood flow (arteriolar vasomotion) that occur in some conditions. Specific Aim 3 is to develop theoretical models including effects of capillary recruitment, and to test their ability to describe the more than 25-fold observed dynamic range of skeletal muscle perfusion. In all these studies, emphasis will be placed on comparing model predictions with available experimental data and using these data to further develop, test and refine the models. This process will be facilitated by well established collaborations with two consultants, Dr. Axel Pries and Dr. Tuhin Roy, who have extensive experience in relevant experimental basic science and clinical areas respectively.